This application is a 371 of PCT/EP99/00781 filed Feb. 5, 1999.
Processes for the preparation of pharmaceutical compositions having microparticles form, comprising the mixing of an active principle with suitable excipients, the extrusion through a mesh in order to form cylindrical filaments and the subsequent spheronization are known.
The fundamental problem of the technique of these processes is that the mixture which is extruded must be sufficiently plastic to allow the stability of the cylindrical filaments form and sufficiently malleable to transform said cylindrical filaments in spherical particles by spheronization. It is possible to use several machines to obtain spherical microparticles: for example, high efficiency granulators, frontal or axial extruders, fluid bed rotogranulators, radial extruders, coaxial double screw extruders, etc. However, notwithstanding the fact that the used plants are of different kind, the known extrusion/spheronization techniques are based on the use of mixtures containing microcrystalline cellulose (AVICELL(trademark)) in percentages ranging from 10 to 20%, whose properties allow the conferring and the maintainment of the necessary plasticity and malleability during the whole process (R. E. Connor and J. B. Schwartz, Drug Dev. Ind. Pharm. 2, 1837, 1985). In order to overcome this problem different techniques which, however, show notable drawbacks have been proposed.
The U.S. Pat. No. 5,049,394 proposes to decrease the microcrystalline cellulose percentages using mixtures of solvents (for example water/ethanol) in spite of water only in order to moisten the dusts.
The U.S. Pat. No. 5,350,584 suggests the use of ionic resins in order to give the desired plasticity to the material to extrude and spheronize. Both the solutions present some applicative limitations because it may be necessary, for some kinds of formulations or in case of incompatibility, to avoid the use of solvents or ionized materials.
A solution proposed to overcome the problems related to the plasticity of the mixture to extrude considers the melting at a suitable temperature of the mixture itself (WO 96/25149 and WO 96/25151). The limitation of this solution lies in the necessity to use thermostable materials and active principles.
Other solutions consider the use of high amounts (to 50%) of plasticizing substances (JP 2527107) allowing to keep plastic the mass to extrude. Such technique strongly limits the amount of active principle which may be introduced in the mass to extrude and moreover it can cause compatibility problems among the materials.
Now we have unexpectedly found that the problems of the prior art are solved using, for the preparation of microparticles by extrusion and spheronization, compositions comprising cross-linked amphiphilic polymers.
Therefore the present invention relates to a process for the preparation of pharmaceutical compositions in form of polymeric microparticles comprising:
a) the preparation of a homogeneous mixture of substances in powder form to which a liquid to a pasty consistence is added;
b) the extrusion of the mixture of the step a) through a perforated mesh in order to obtain cylindrical filaments;
c) the spheronization of the cylindrical filaments of the step b) in order to obtain microparticles in spherical form, and
d) the drying of the microparticles of the step c),
e) optionally drug is deposited on the surface of the microparticles, characterized in that said mixture of substances in powder form consists of one or more cross-linked amphiphilic polymers and optionally one or more drugs, excipients, a bioadhesive substance and/or a substance having high density.
The process according to the present invention shows several advantages with respect to the prior art because it does not ask for the presence of plasticizing, linking substances, solvents or linear polymers and it allows the incorporation of high percentages of drugs having different characteristics of solubility and wettability.